It has long been recognized that certain diseases potentially could be therapeutically treated by transferring cells, tissues, or organs into a patient having the particular disease. Attempts to carry out such transfers have been ongoing for many years, and have met with some success. However, transferred cells, tissues, or organs are often rejected by the patient's immune system.
Devices carrying cells within or on a polymeric matrix have been suggested to be useful for obtaining successful implantation of cells into a patient. Lanza, R. et al., Diabetes 41:1503 (1992); Langer, R. and Vacanti, J. Science 260:920 (1993). As used herein, implantation refers to the grafting or insertion of an object, with or without cells, into the body of a patient. Transplantation refers to the transfer of unenclosed tissues or organs, without additional objects such as supports or enclosures, into the body of a patient. The polymeric matrix may be composed of a naturally occurring substance such as alginate or collagen. Alternatively, the matrix may be composed of a synthetic polymer such as acrylonitrile-vinyl chloride copolymer or polyacrylates. Several types of devices have been disclosed, including extravascular compartments, macrocapsules, and microcapsules. The devices generally have membranes permeable to low molecular weight molecules and proteins, but not permeable to cells, high molecular weight molecules, or subcellular complexes.
In recent years, gene transfer into cells has been proposed as a useful technique for treatment of certain diseases and medical conditions. The transfer of extrinsic genetic material into cells is often referred to as transduction, transfection, or genetic engineering, and the employment of such cells to treat disease in vivo is often referred to as gene therapy. Various gene therapy methods have been proposed or are in testing. Anderson, W., Science 256:208 (1992).
Difficulties have been noted, however, in transplantation and implantation of cells, whether or not genetically engineered. Conventional implant devices and methodologies usually fail to keep the implanted cells alive for a time sufficient to provide the intended therapeutic benefit. For a period of time after implantation, the tissues in the vicinity of the implanted device can be characterized as ischemic. That is, the local vasculature is inadequate to ensure a sufficient flow of blood to the tissues in the region closely surrounding the implanted device. Conventional devices generally induce a fibrous capsule composed of layers of fibroblasts, collagen, macrophages, foreign body giant cells and small lymphocytes. The fibrous capsule has been thought to cause ischemic necrosis and thereby to reduce or inhibit the flux of nutrients, cellular waste products and therapeutic substances between the device and the patient. Lanza, R. et al., supra; Langer, R. and Vacanti, J., supra.
The body's response to implantation of a device involves several phases. An acute-phase inflammatory reaction is initiated following activation of tissue macrophages and release of the cytokines TNF-.alpha., interleukin-1 and interleukin-6. The result is a fever response, increased vascularization, and an influx of macrophages and lymphocytes to the site of implantation. The recruited macrophages may release factors that are damaging to implanted cells. In humans, the acute phase of inflammation usually lasts for 2-3 days during which the wound becomes sealed by a fibrin clot within which polymorphonuclear leukocytes act to prevent invasion of microorganisms.
The predominant bioactive cells in the inflammatory process are mononuclear cells. Mononuclear cells can differentiate as macrophages and become actively phagocytic. Macrophages in fact play a pivotal role in the response of tissue to implants. Anderson, J. Trans. Am. Soc. Artif. Intern. Organs 34:101 (1988). Some mononuclear cells coalesce and differentiate as multinucleated giant cells, which are also phagocytic. The phagocytic mononuclear cells dispose of those cellular and tissue components that are not readily solubilized by enzymes released by granulocytes or activated by local circulatory factors. This phagocytic process generally characterizes the terminal phase of the acute inflammatory reaction. However, continued presence of foreign materials can cause persistence of this inflammatory reaction, recognized as chronic inflammation. Mononuclear cells and their differentiated progeny may be referred to as inflammatory cells.
The response to implantation of a device containing cells or other antigenic materials also involves immune system recognition, which is apparent about 10 to 14 days after implantation in mammals. The severity of the immune response generally is determined by the immunogenicity of the implanted cells. Isogeneic cells or allogeneic cells generally lead to a low to moderate immune response and the host tissue immediately adjacent to the device being vascularized. However, xenogeneic cells generally induce a much more severe host cellular response, consisting of an extensive accumulation of inflammatory cells such as lymphocytes and macrophages. The halo of local inflammation around implanted devices housing xenogeneic cells is largely avascular.
Attempts have been made to inhibit the inflammatory response and to inhibit immune recognition and rejection of transplanted or implanted cells by supplying an agent such as cyclosporine A. A seeming disadvantage in use of cyclosporine A is that it is reported to inhibit neovascularization, which is important for successful implantation. In fact, cyclosporine A has been reported to interfere with establishment of isogeneic pancreatic transplants by inhibiting neovascularization. Carotenuto, P., et al., European Assoc. Study Diabetes, 28th Ann. Meeting, Abs. 730 (1992); Rooth, P. et al., Diabetes 38 (Suppl. 1): 202-5 (1989).
Thus, there is a continuing need for devices and methods that enhance neovascularization of implants so as to increase the rate of successful implantation and to increase the long term viability of implanted isogeneic, allogeneic and xenogeneic cells.